Ischemia limits the ability of a myocardium to generate sufficient high energy phosphates to maintain myocyte viability. Although reperfusion, especially early after the onset of occlusion has revolutionized the treatment of acute myocardial ischemia, beneficial effects are limited by the amount of ischemic damage that occurs prior to reperfusion. In this context, the enhancement of myocardial metabolism during ischemia as means of protecting the myocardium assumes greater importance. In recent years, a variety of metabolic therapies that enhance myocardial metabolism during ischemia have been proposed. They focus on (a) increasing myocardial glycolysis by increasing glucose uptake during ischemia or (b) limiting the inhibitory effects of fatty acids to increase glucose metabolism and flux through pyruvate dehydrogenase (PDH) on reperfusion, and (c) inhibiting sodium and calcium influx pathways during ischemia that deplete high energy phosphates. Recent studies from our laboratory demonstrated a novel metabolic approach of protecting ischemic rat hears by inhibiting aldose reductase, a key regulatory enzyme in the substrate flux via the polyol pathway. This novel intervention limited infarct size and improved function and metabolic recovery after ischemia. The aim of this proposal research is to delineate the role of aldose reductase protects ischemic myocardium. Specifically, studies will be performed in isolated rat/mice hearts to investigate if (a) ischemia increases aldose reductase activity, and if the hearts over-expressed for aldose reductase exhibit increased ischemic injury in mice transgenic for aldose reductase, the rate of glycolysis and changes in metabolites, the activity of the Na+, K+-ATPase as well as other sodium transporters, and changes in intracellular sodium and calcium during ischemia in aldose reductase inhibited hearts. Biochemical assays will be used to measure enzyme activities and metabolites, while nuclear magnetic resonance (NMR) spectroscopy will be used to measure time dependent changes in intracellular sodium and calcium. The ability to examine the relationship between metabolism and function using biochemical assays and NMR spectroscopy will enhance our understanding of the mechanism by which aldose reductase inhibition protects the myocardium from ischemic injury. Further, this novel approach of protecting the myocardium from ischemic injury, may become a useful therapeutic intervention in treating myocardial infarction in patient.